1. Field of the Invention
This invention relates to a method for treating, alleviating or preventing anxiety by administering a pharmaceutical composition comprising a therapeutically effective amount of pterostilbene, an analog of resveratrol, found in grapes and some Vaccinium berries.
2. Description of the Relevant Art
Anxiety disorders are common in community settings and in primary and secondary medical care, and frequently turn into chronic clinical conditions (Nutt et al. 2002. Int. J. Neuropsychopharmacol. 5:315-325). Anxiety disorders are the most common type of psychiatric disorders, with an incidence of 18.1% and a lifetime prevalence of 28.8% (Kessler et al. 2005. Arch. Gen. Psychiatry 62: 617-627; Ohayon, M. M. 2006. J. Psychiatr. Res. 40: 475-476). Anti-anxiety drugs have been used by human beings for thousands of years. Benzodiazepine group of drugs are fast acting, effective and the most commonly prescribed anxiolytics (Bandelow et al. 2008. World J. Biol. Psychiatry 9:248-312; Baldwin et al. 2005. J. Psychopharmacol. 19:567-596; Rudolph and Mohler. 2006. Curr. Opin. Pharmacol. 6:18-23). However, their long-term use is associated with side effects such as sedation, development of tolerance, abuse liability, and withdrawal symptoms (Nutt et al., supra; Bandelow et al., supra; Baldwin et al., supra). Currently, a selective serotonin reuptake inhibitor group of antidepressants is used as a first-line treatment for most anxiety disorders. However, this group also has drawbacks. In particular, there is a slow onset of therapeutic action, thus several weeks of treatment are required for the anxiolytic effects to occur (Nutt et al., supra; Bandelow et al., supra; Baldwin et al., supra). Therefore, there is still a need for anxiolytic compounds that have rapid therapeutic action but are devoid of untoward effects.
Large numbers of natural compounds have provided not only useful pharmacological tools (Furukawa etal. 1993. J. Biol. Chem. 268:26026-26031), but also potential therapeutic leads for drug development (Liu, J. 1993. Trends Pharmacol. Sci. 14:182-188). Stilbenes are a group of phytochemicals having an α, β-diphenylethylene core structure. Stilbenes have been reported in a large number of unrelated plant genera including grapes; peanuts, and Vaccinium berries (Chong et al. 2009. Plant Sci. 177:143-155). Resveratrol, a widely studied stilbene, has been reported to exert anti-oxidant, anti-inflammatory, chemopreventive, and anti-aging effects in a number of biological systems (Aggarwal et al. 2004. Anticancer Res. 24:2783-2840; Baur and Sinclair. 2006. Nat. Rev. Drug Disco. 5:493-506; Bishayee, A. 2009. Cancer Prev. Res. 2:409-418). Recently, pterostilbene, a natural analog of resveratrol, found in some Vaccinium berries such as blueberries and deerberries (Rimando et al. 2004. J. Agric. Food Chem. 52:4713-4719) has been receiving much attention for having diverse effects like those shown for resveratrol. Pterostilbene has analgesic, antidiabetic, antioxidant, anti-inflammatory, hypolipidemic, and cancer chemopreventive properties (Amarnath Sateesh and Pari. 2006. J. Pharm. Pharmacol. 58:1483-1490; Remsberg et al. 2008. Phytotherapy Res. 22: 169-179; Rimando et al. 2002. J. Agric. Food Chem. 50:3453-3457; Rimando et al. 2005. J. Agric. Food Chem. 53:3403-3407). Pterostilbene also has significant effect on colon cancer development (Paul et al. 2009. Cancer Prey. Res. 2:650-657), invasion and metastasis (Pan et al. 2009. Carcinogenesis 30:1234-1242), and in reversing cognitive deficits in aged rats (Joseph et al. 2008. J. Agric. Food Chem. 56:10544-10551). However, the anxiolytic potential of pterostilbene has not yet been investigated.
Many natural compounds, including stilbenes, interact with protein kinases involved in different signaling pathways such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and p38 mitogen-activated protein kinase (MAPK) (Paul et al. 2009, supra). It is well established that extracellular signal-regulated kinase 1/2 (ERK 1/2 ), a member of the MAPK family, plays an important role in transcriptional regulation in many cell types, including neurons (Hetman and Gozdz. 2004. Eur. J. Biochem. 271:2050-2055). Accumulating evidence indicates that the ERK signaling pathway is activated under various stimuli (Davis, R. J. 1993. J. Biol. Chem. 268:14553-14556; Hetman and Gozdz, supra), including exposure to stress (Gerrits et al. 2006. Neuroscience 142:1293-1302). In addition, the ERK signaling pathway in the hippocampal and lateral amygdala is speculated to play a role in anxiety (Paul et al. 2007. Biol. Psychiatry 61:1049-1061; Tronson et al. 2007. Neuropsychopharmacol. 133:1570-1583). This notion is further consolidated by the findings that the levels of phophorylated ERK increased significantly during anxiety. Therefore, the ERK signal transduction pathway might play an important role in anxiety and its inhibition could produce anxiolytic effects (Ailing et al. 2008. J. Psychiatr. Res. 43:55-63).
Thus, in view of the role of signaling pathways in anxiety and the need for agents which can be used to treat anxiety, the goal of this work was to determine the effects of pterostilbene as an inhibitor of anxiety.